1. Field of the Invention
The present invention relates to novel compounds that function as proteolytic enzyme inhibitors, and particularly to a new class of thrombin inhibitors.
2. Related Art
Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Cathepsin G is another human neutrophil serine protease. Compounds with the ability to inhibit the activity of these enzymes are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase and plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons. Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor (Coughlin, Seminars in Hematology 31(4):270-277 (1994)), and autoamplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases.
Factor Xa is another serine protease in the coagulation pathway. Factor Xa associates with factor Va and calcium on a phospholipid membrane thereby forming a prothrombinase complex. This prothrombinase complex then converts prothrombin to thrombin (Claeson, Blood Coagulation and Fibrinolysis 5:411-436 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xa are thought to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still permit significant new thrombin generation (Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)).
In vivo diagnostic imaging methods for intravascular thrombi have been previously reported. These imaging methods use compounds that are detectably labeled with radioactive or paramagnetic atoms. For example, platelets labeled with the gamma emitter, In-111, can be employed as an imaging agent for detecting thrombi (Thakur, M. L. et al., Thromb Res. 9:345 (1976); Powers et al., Neurology 32:938 (1982)). The thrombolytic enzyme streptokinase labeled with Tc-99m has been proposed as an imaging agent (Wong, U.S. Pat. No. 4,418,052 (1983)). The fibrin-binding domains of Staphylococcus aureus derived protein A labeled with the gamma emitters, I-125 and I-131, have been proposed as imaging agents (Pang, U.S. Pat. No. 5,011,686 (1991)). Monoclonal antibodies having specificity for fibrin (in contrast to fibrinogen) and labeled with Tc-99m have been proposed as imaging agents (Berger et al., U.S. Pat. No. 5,024,829 (1991); Dean et al., U.S. Pat. No. 4,980,148 (1990)). The use of the paramagnetic contrasting agent, gadolinium diethylenetriaminepentaacetic acid in magnetic resonance imaging of patients treated by thrombolysis for acute myocardial infarction has been reported (De Roos, A. et al., Int. J. Card. Imaging 7:133 (1991)). Radiolabeled and paramagnetically labeled alpha-ketoamide derivatives have also been proposed as thrombus imaging agents (Abelman et al., U.S. Pat. No. 5,656,600).
Edwards et al., J. Amer. Chem. Soc. 114:1854-63(1992), describes peptidyl .alpha.-ketobenzoxazoles that reversibly inhibit the serine proteases human leukocyte elastase and porcine pancreatic elastase.
European Published Application 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
Australian Published Application 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or .alpha.-keto carboxyl derivatives.
Brown et al., J. Med. Chem. 37:1259-1261 (1994) describes orally active, non-peptidic inhibitors of human leukocyte elastase which contain trifluoromethylketone and pyridinone moieties.
H. Mack et al., J. Enzyme Inhibition, 9:73-86 (1995) describes rigid amidino-phenylalanine thrombin inhibitors which contain a pyridinone moiety as a central core structure.
PCT International Published Application WO 97/01338 describes pyridinone compounds having the formula: ##STR2##
where
W is R.sup.1, R.sup.1 OCO, R.sup.1 CO, R.sup.1 SO.sub.2, or (R.sup.1).sub.m (CH.sub.2).sub.n NH.sub.q CO; PA1 R.sup.1 is R.sup.2 (CH.sub.2).sub.n, (R.sup.2)(OR.sup.2)CH(CH.sub.2).sub.p, (R.sup.2).sub.2 CH(CH.sub.2).sub.n, and R.sup.2 O(CH.sub.2).sub.p ; PA1 R.sup.2 is hydrogen, optionally substituted phenyl, naphthyl, biphenyl, a mono- or bicyclic heterocyclic ring, COOR.sup.6, C.sub.1-4 linear or branched alkyl, C.sub.3-7 cycloalkyl, or C.sub.7-12 bicyclic alkyl; PA1 R.sup.3 is hydrogen, C.sub.1-4 linear or branched alkyl, C.sub.3-7 cycloalkyl, or trifluoromethyl; PA1 A is one of: ##STR3## PA1 R.sup.6 is hydrogen, or C.sub.1-4 linear or branched alkyl. PA1 Het is selected from the group consisting of ##STR6## PA1 and R.sub.3 is selected from the group consisting of: ##STR7## PA1 condensing or coupling a compound of formula: ##STR8## PA1 or a salt thereof, with a compound of Formula XI: ##STR9## PA1 A is one of ##STR11## PA1 R.sup.1 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle or heterocycloalkyl, any of which may be optionally substituted; PA1 Z is --SO.sub.2 --, --OCO--, --CO--, --NR.sup.2 CO-- or a covalent bond, PA1 Het is selected from the group consisting of ##STR12## PA1 where PA1 R.sup.7 is hydrogen, C.sub.1-4 alkyl, or C.sub.2-4 alkenyl; PA1 R.sup.a, R.sup.b and R.sup.c are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or --CO.sub.2 R.sup.w, where PA1 where PA1 each n is from zero to 4, preferably zero to 2; PA1 each m is from zero to 4, preferably zero to 2; and PA1 each j is zero to 4, preferably zero to 2; PA1 provided that n, m and j are not all zero. PA1 wherein R.sup.5 is selected from the group consisting of hydrogen, methyl, ethyl, propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl, S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl, R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrrolyl, 3-pyrrolyl, 1-hexyl, S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl. A particularly preferred Het according to this aspect has hydrogen, methyl, ethyl, propyl or isopropyl as R.sup.5. PA1 where R.sup.d -R.sup.h are defined as above. When R.sup.a, R.sup.b and R.sup.c are --CO.sub.2 R.sup.w, where R.sup.w is one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics. A preferred value for each of R.sup.d, R.sup.c and R.sup.g is hydrogen, R.sup.f is methyl, and preferred values for R.sup.h include benzyl and tert-butyl. PA1 and R.sup.a, R.sup.b and R.sup.c are all hydrogen. A very preferred aspect is directed to such compounds where R.sup.1 is substituted or unsubstituted benzyl or phenyl, and R.sup.a, R.sup.b and R.sup.c are all hydrogen. PA1 Z' is --OCO--, --CO--, --SO.sub.2 --, --NHCO--, or a covalent bond; PA1 R.sup.21 is R.sup.22 (CH.sub.2).sub.k, where k is 0-4, (R.sup.22)(OR.sup.22)CH(CH.sub.2).sub.p, where p is 1-4, (R.sup.22).sub.2 CH(CH.sub.2).sub.k, where k is 0-4 and R.sup.22 can be the same or different, and wherein (R.sup.22).sub.2 can also be a ring substituent on CH represented by C.sub.3-7 cycloalkyl, C.sub.7-12 bicyclic alkyl, or a 5- to 7- membered mono-, or 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S, and R.sup.22 O(CH.sub.2).sub.p, wherein p is 1-4; PA1 R.sup.22 is hydrogen; phenyl, unsubstituted or substituted with one or more of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, trifluoromethyl, hydroxy, COOH, or CONH.sub.2 ; naphthyl; biphenyl; a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S; C.sub.1-4 alkyl; C.sub.3-7 cycloalkyl, or C.sub.7-12 bicyclic alkyl; PA1 R.sup.25 is hydrogen, C.sub.1-4 alkyl C.sub.3-7 cycloalkyl, or trifluoromethyl; PA1 R.sup.a, R.sup.b and R.sup.c are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or --CO.sub.2 R.sup.w, where PA1 where PA1 n is from zero to 4; PA1 m is zero to 2; and PA1 j is zero to 2. PA1 coupling or condensing a compound of formula: ##STR28## PA1 or a salt thereof, where R.sup.a, R.sup.b and R.sup.c are as defined herein or optionally protected, and n, m and j are as defined herein, with a compound of Formula XI: ##STR29##
where Y is hydrogen, hydroxy, or CN; and PA2 where R.sup.3, R.sup.4, R.sup.5, R.sup.51, R.sup.a, R.sup.b, R.sup.c, n, m and j are as defined herein. PA2 where R.sup.2 is hydrogen, alkyl, aralkyl, aryl, hydroxy(C.sub.2-10)alkyl, amino(C.sub.2-10)alkyl, monoalkylamino(C.sub.2-10)alkyl, dialkylamino(C.sub.2-10)alkyl or carboxyalkyl; PA2 R.sup.3, R.sup.4 and R.sup.5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, --CO.sub.2 R.sup.x, --CH.sub.2 OR.sup.x or --OR.sup.x, PA2 R.sup.6 is hydrogen, alkyl, aralkyl, aryl, cyano(C.sub.2-10)alkyl, hydroxy(C.sub.2-10)alkyl, alkoxy(C.sub.2-10)alkyl, mono- and di-alkylamino(C.sub.2-10)alkyl, or carboxyalkyl; PA2 R.sup.w is alkyl, cycloalkyl, phenyl, benzyl, ##STR13## PA2 R.sup.d and R.sup.e are independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.f is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.g is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, and R.sup.h is aralkyl or C.sub.1-6 alkyl; PA2 R.sup.w is alkyl, cycloalkyl, phenyl, benzyl, ##STR19## PA2 R.sup.d and R.sup.e are independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.f is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.g is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, and R.sup.h is aralkyl or C.sub.1-6 alkyl; PA2 where R.sup.51 is H or R.sup.1 -X-, where R.sup.1, X, R.sup.3, R.sup.4, R.sup.5, R.sup.a, R.sup.b, and R.sup.c are as defined herein. In general, protecting groups for the R.sup.a, R.sup.b, and R.sup.c groups may be employed where any one of R.sup.a, R.sup.b, and R.sup.c are hydrogen.
PCT International Published Application WO97/30708 discloses pyridinone compounds of the general formula: ##STR4##
The compounds are disclosed to be useful for inhibiting thrombin and associated thrombotic occlusions.
PCT Published Application WO 96/18644 describes compounds having the formula: ##STR5##
wherein
The compounds are described as specific inhibitors of thrombin.
A need continues to exist for additional non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states.